The processes typically employed in producing 1-{4-2-(Cyclopropylmethoxy)ethyl!phenoxy}-3-isopropylamino-propane-2-ol (Betaxolol) involved protecting the phenol functional group so that the alcohol could be alkylated. This involves extra protection and subsequent deprotection steps which make the reaction complicated as well as gives low yields which may further require chromatography to purify product.
U.S. Pat. No. 4,252,984 to Manoury et al., describes benzylation of the phenolic alcohol of 4-hydroxyphenethanoic acid. The ethanoic acid group is then reduced to an alcohol and subsequently alkylated with (bromomethyl)cyclopropane. Reduction with H.sub.2 in the presence of a catalyst deprotects the compound back to a phenolic compound. In a final step, addition of isopropylamine produces the end product, Betaxolol. A silica gel column is used to purify the compound.
U.S. Pat. No. 4,760,182 to Ippolito et al., describes a process for producing Betaxolol by converting 4-hydroxyphenethanol to a phenoxide anion with a base and then reacting the phenoxide anion with epichlorohydrin to produce 1-4-(2-hydroxyethyl)phenoxy!-2,3-epoxypropane. 1-4-(2-hydroxyethyl)phenoxy!-2,3-epoxypropane is reacted with a primary amine to produce an intermediate of Betaxolol. Protection and deprotection steps are necessary to obtain the final product.
U.S. Pat. No. 5,034,535 to Keding et al., describes reacting 4-2-methoxyethyl!phenol with (S)-5-hydroxymethyl-3-isopropyloxazolidin-2-one sulfonic acid ester to prepare an intermediate in the preparation of S-metoprolol.
The processes typically employed in producing Betaxolol involve extra protection and deprotection steps which make the reaction complicated. Specifically, the epoxide of 1-4-(2-hydroxyethyl)phenoxy!-2,3-epoxypropane is not stable toward alkylating reagent since the usual alkylation condition will cause polymerization of the epoxy-alcohol. This is due to the molecule possessing both a nucleophilic and an electrophilic center. The alkoxide of 1-4-(2-hydroxyethyl)phenoxy!-2,3-epoxypropane can react with the alkylating reagent as well as the epoxide moiety of 1-4-(2-hydroxyethyl)phenoxy!-2,3-epoxypropane, leading to the formation of multiple products/polymers.
It is therefore advantageous and preferable to have a process wherein the protection and deprotection steps can be eliminated. In addition, it would be a further advantage to have a process which produces highly pure betaxolol.